Contribution of Ipsilateral Primary Motor Cortex Activity to the Execution of Voluntary Movements in Humans: a Review of Recent Studies

J Phys Fitness Sports Med, 3(3): 297-306 (2014) DOI: 10.7600/jpfsm.3.297 JPFSM: Review Article Contribution of ipsilateral primary motor cortex activity to the execution of voluntary movements in humans: A review of recent studies

Kazumasa Uehara1,2 and Kozo Funase1*

1 Human Motor Control Laboratory, Division of Human Sciences, Graduate School of Integrated Arts and Sciences, Hiroshima University, 1-7-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8521, Japan 2 Japan Society for the Promotion of Science, 8 Ichiban-cho, Chiyoda-ku, Tokyo 102-8472, Japan

Received: May 13, 2014 / Accepted: May 29, 2014

Abstract In primates, unilateral voluntary movements are preferentially controlled by the primary motor cortex (M1) contralateral to the side performing the movement. However, it has been reported that the M1 ipsilateral to the side performing the movement (ipsi-M1) is also activated during unilateral voluntary movements. Recently, studies involving transcranial magnetic stimulation (TMS) or functional magnetic resonance imaging (fMRI) techniques have gradually elucidated the neural mechanisms responsible for modulating ipsi-M1 activity. In particular, the modulation of ipsi-M1 activity is likely to occur in a task-dependent manner, and is also closely associated with advancing age. In addition, ipsi-M1 excitability is suppressed during the acquisition phase of motor learning. Previous studies have suggested that the modu- lation of ipsi-M1 activity occurs via changes in the activation of the corpus callosum pathways linking the bilateral M1. In this article, we will broadly review the features of ipsi-M1 activity, observed during the execution of unilateral movements, as well as the detailed neural mecha- nisms underlying the modulation of ipsi-M1 activity. Understanding the role played by ipsi-M1 activity during voluntary movements would improve our knowledge of human motor control systems. Keywords : ipsilateral primary motor cortex, voluntary movement, task-dependency, corpus cal- losum, human motor control, motor learning

pass perpendicular to the plane of the coil, which induces Introduction eddy currents within the brain. When suprathreshold TMS During unilateral voluntary movements involving the is delivered over the M1 representation of hand muscles, upper limbs, the muscles in the upper limbs are predomi- the magnetic pulse evokes a muscle response in the con- nantly under the control of crossed corticospinal tracts tralateral hand muscle, which can be recorded using elec- originating from the primary motor cortex contralateral tromyography12). Such muscle responses are called motor (contra-M1) to the side performing the movement, be- evoked potentials (MEP). The TMS technique is widely cause approximately 80% of corticospinal fibers cross used to assess neurophysiological changes in M1 excit- over to the contralateral side at the pyramidal decussa- ability. On the other hand, fMRI is a non-invasive high tion1). However, there is a growing body of evidence to spatial resolution mapping method in which MRI signals suggest that the ipsilateral M1 (ipsi-M1) is also involved are used to detect blood flow and oxygen metabolism as in controlling upper limb movements (Fig. 1)2-11). a means of measuring the neural activity of the whole Due to recent developments in neuroimaging, e.g., brain13,14). Ogawa et al.15) were the first to demonstrate the functional magnetic resonance imaging (fMRI), and neu- blood oxygen level dependent (BOLD) signals that are rophysiological techniques, e.g., transcranial magnetic the basis of the fMRI technique. The blood oxygen levels stimulation (TMS), findings regarding the features of ipsi- within particular areas of the brain are remarkably sensi- M1 activity, induced during unilateral movements, and tive to the changes in neural activity induced by motor, the mechanisms by which ipsi-M1 activity is modulated motor imagery, or cognitive tasks. As with the TMS tech- have been reported since the late 1990s. In brief, TMS nique, fMRI has been widely used across a range of re- is a non-invasive brain stimulation technique in which search fields to assess brain and spinal activity in humans. neurons are temporarily activated using a magnetic coil. A representative TMS study by Stedman et al.2) found A magnetic field is produced within the lines of flux that that MEPs, induced in a relaxed finger muscle in response to single-pulse TMS of the contra-M1, were increased *Correspondence: [email protected] when the opposite homologous muscle was voluntarily 298 JPFSM: Uehara K and Funase K

Ipsilateral hemisphere Contralateral hemisphere (resting M1) (active M1)

Corpus callosum pathway

Spinal Fig. 1 A schematic illustration of the descending tracts motoneuron (black arrows) originating from the M1 and the corpus callosum pathways (blue arrow) connect- ing both hemispheres. In general, unilateral vol- untary movements are preferentially controlled by the M1 contralateral to the movement side. However, the M1 ipsilateral to the movement side is also involved in unilateral movements. The corpus callosum pathways could be one of the pathways involved in the modulation of ipsi- M1 activity. Movement side activated. It is suggested that such increases in the MEPs Given the accumulating evidence regarding the effects of relaxed finger muscles probably result from both corti- of ipsi-M1 activity during voluntary movements, we con- cal and spinal activity. In a study using fMRI, Kobayashi sider that activation of the ipsi-M1 during unilateral vol- et al.16) reported that during a repetitive unilateral rhyth- untary movements is worthy of attention from researchers mic movement, activation of both the contra- and ipsi- investigating human motor control systems. The primary M1 was detected in half of the participants. According to goal of this article is to review the contribution of ipsi-M1 the studies described above, the execution of unilateral activity and the neural mechanisms underlying the modu- voluntary movements involving the upper limbs is ac- lation of ipsi-M1 excitability during various voluntary companied by an increase in ipsi-M1 excitability. Studies movement tasks involving the use of the upper limbs. In examining the mechanisms responsible for such changes addition, we will review the relationship between aging have reported that modulation of the corpus callosum and ipsi-M1 activity and the role played by ipsi-M1 activ- pathways linking both hemispheres7,10,16-19) or ipsilateral ity in motor learning. Furthermore, we will discuss the projections to the ipsilateral spinal cord20) are involved functional significance of ipsi-M1 activity during unilat- in MEP changes in the opposite limb during the perfor- eral movement. mance of unilateral movements. Very recently, it has been reported that uncrossed descending pathways originating Task-dependent modulation of ipsi-M1 activity from the ipsi-M1 to the ipsilateral spinal cord play an im- portant role in controlling skilled upper limb movement In recent human TMS studies examining the relation- as well as selective muscle activity in the proximal upper ship between simple muscle contractions and ipsi-M1 ex- limb21-23). citability, it was reported that unilateral isometric muscle In addition, clinical evidence has been obtained regard- contractions of the wrist or finger muscles significantly ing the contribution of the ipsi-M1 to post-stroke recov- increase the excitability of the ipsi-M1 for the opposite ery. Specifically, it has been suggested that upregulation homologous muscle and that the degree of ipsi-M1 excit- of the activity of the contralesional M1 (i.e., ipsilateral to ability increased with muscle contraction strength8,17,18,26). the paretic side) might be important for improving paretic With regard to muscle contraction type, a previous study arm function after stroke24,25). These findings indicate that assessed the changes in the MEP induced in the relaxed the M1 ipsilateral to the paretic side discharges neural im- opposite flexor carpi radialis (FCR) during shortening or pulses to the paretic limb via either uncrossed descending lengthening muscle contractions of the forearm muscles. or corpus callosum pathways on behalf of the ipsilesional As a result, it was found that of the MEP evoked in the M1. relaxed FCR during the lengthening muscle contractions JPFSM: Contribution of ipsilateral motor cortex to human motor control 299 exhibited significantly smaller amplitudes than those have also been studied using TMS. As a result, an in- evoked during the shortening muscle contractions27), indi- crease in ipsi-M1 excitability was detected during the ex- cating that muscle contraction type affects ipsi-M1 excit- ecution of a unilateral imagined voluntary movement of ability. Thus, even during the execution of simple muscle the index finger28). Furthermore, a relationship was dem- contraction tasks, ipsi-M1 excitability is affected by the onstrated to exist between the inhibitory corpus callosum strength and type of the contractions. pathways connecting the bilateral M1, i.e., interhemi- The relationship between the performance of skilled spheric inhibition (IHI), and motor imagery. Specifically, motor tasks involving the finger muscles and ipsi-M1 the IHI from the contra- to the ipsi-M1 was significantly activation has been established. Morishita et al. assessed increased during unilateral imagined voluntary movement ipsi-M1 excitability using single-pulse TMS while right- compared with that observed during the resting state (i.e., handed participants transferred small grass balls from no imagery)29). one box to another using chopsticks with either their left Thus, the findings of the abovementioned studies indi- or right hand. As a result, it was demonstrated that ipsi- cate that ipsi-M1 excitability is modulated in a task-de- M1 excitability was significantly increased during the pendent manner during unilateral voluntary or imagined performance of skilled motor tasks with either the left movement. or right hand, and that the induced ipsi-M1 excitability was significantly increased when the left hand was used Age-related modulation of ipsi-M1 activity to perform the task. In addition, it should be noted that a pseudo-skilled motor task that did not involve the use The activity of the ipsi-M1 is closely associated with of chopsticks; i.e., a repetitive fingertip-based grasp- aging. There is a growing body of evidence that age-as- ing movement involving the thumb and the index and sociated modulation of brain activity in both hemispheres middle fingers induced weaker ipsi-M1 excitability than influences the decline in motor performance and motor the skilled motor task irrespective of which hand was deficits seen in elderly people30-33). An fMRI study that used9). In the latter study, the skilled motor task probably compared the findings of younger and elderly participants required sensitive motor control of the finger muscles, detected increased ipsilateral activation of the sensorimo- resulting in the enhancement of ipsi-M1 excitability. In- tor area (SM1), dorsolateral prefrontal cortex (PMd), and terestingly, as described above the degree of ipsi-M1 ex- supplemental motor area (SMA) in the elderly partici- citability induced by the skilled motor task was dependent pants during unilateral passive wrist movement. During on which hand was performing the task, indicating that unilateral rhythmic movement performed according to a manual dexterity can have a substantial effect on ipsi-M1 1 Hz auditory cue or at the maximal possible frequency, excitability. the elderly subjects displayed significantly increased ipsi- Using single-pulse TMS, Uehara et al. investigated lateral activation of the SM1, SMA, Brodmann area (BA) the modulation of ipsi-M1 excitability during repetitive 45, BA5, and BA7 compared with to younger subjects. rhythmic unilateral contractions of a finger muscle, which Interestingly, during the performance of a more difficult were paced according to auditory cues. Accordingly, it somatosensory-guided unilateral precision task involving was demonstrated that ipsi-M1 excitability was modu- the fingers, the ipsilateral SM1 activity of the younger lated in a rhythmic manner and that the modulation was subjects was significantly greater than that of the elderly dependent on the frequency of the rhythm itself. In par- subjects30). ticular, performing the rhythmic muscle contractions at 1 In an electroencephalogram study, elderly subjects ex- or 3 Hz resulted in increases in ipsi-M1 excitability, while hibited markedly greater activation of the ipsilateral sen- performing them at 2 Hz led to a reduction in ipsi-M1 sorimotor area, i.e., in the low (10-11 Hz) and high (12-13 excitability7). The relationship between ipsi-M1 activity Hz) alpha bands, than younger subjects during unilateral and the frequency demands of rhythmic muscle contrac- repetitive finger movement according to a 1 Hz auditory tions is not yet fully understood; however, in the above- cue33). Likewise, it was shown that advancing age was as- mentioned study the accuracy of the rhythmic muscle sociated with the degree of ipsi-M1 excitability induced contractions was assessed by calculating coefficients of during an active motor task34). Furthermore, other fMRI- variance (CV) for the inter-tap-interval (ITI). The CV based studies have found that advancing age was accom- observed in the 2 Hz condition was significantly lower panied by a reduction in ipsi-M1 deactivation during the than those obtained for the 1 and 3 Hz conditions, indicat- performance of active motor tasks35,36). These findings ing that the 2 Hz conditions resulted in rhythmic muscle suggest that active motor tasks induce greater ipsi-M1 ac- contractions with low variability. Thus, the modulation of tivity in older subjects. ipsi-M1 excitability induced in response to the rhythmic The age-dependent modulation of ipsi-M1 excitability contractions displayed a similar pattern to the CV of the could be due to age-dependent changes in the activity of ITI. This finding indicates that ipsi-M1 excitability is af- corpus callosum pathways. It has been suggested that the fected by the accuracy of rhythmic muscle contractions7). fibers of the corpus callosum that connect the bilateral The effects of motor imagery on ipsi-M1 excitability hemispheres contribute to the modulation of ipsi-M1 300 JPFSM: Uehara K and Funase K excitability. The corpus callosum is the biggest bundle left hand, to induce motor learning and then examined of white matter in the brain37), and the interhemispheric the resultant changes in ipsi-M1 excitability by recording pathways (i.e., interhemispheric inhibition, IHI) that are TMS-induced MEP from the relaxed finger muscles con- mediated via this bundle can be assessed using a paired- tralateral to the movement side. As a result, it was found pulse TMS technique. IHI has two phases, an inhibitory that the MEPs induced in the contralateral relaxed finger component that depends on the interstimulus interval muscles were decreased after the motor learning task (ISI) between the conditioning and test stimuli38). Previ- whereas motor performance (the number of ball rotations ous studies have detected a relationship between the IHI per 30s) was increased, indicating that the motor learning of the bilateral M1 and aging. For example, in one study of unilateral movements suppresses ipsi-M1 excitabil- younger subjects exhibited stronger IHI of the ipsi-M1 ity48). Another study examined whether the suppression of during unilateral voluntary muscle contractions than el- ipsi-M1 excitability via inhibitory repetitive TMS (rTMS), derly subjects39). Likewise, age-related differences in the i.e., frequency of 1 Hz for 10 min, improved skilled motor microstructures of the fiber tracts of the corpus callosum learning in the ipsilateral hand; and it was demonstrated linking the bilateral M1 and the degree of IHI have been that motor performance (i.e., the key press execution reported in studies combining diffusion tensor imaging time) was significantly improved by rTMS of the ipsi-M1 and TMS techniques. In the younger adults, a positive prior to the motor learning task compared with the motor correlation was detected between microstructural integrity performance levels observed in the control (vertex stimu- of the fiber tracts of the corpus callosum and IHI, indi- lation) and contra-M1 stimulation conditions49). These cating that better corpus callosum tract microstructural findings could help to explain the relationship between integrity leads to the induction of strong IHI. Conversely, motor learning and ipsi-M1 activity; i.e., they suggest that the elderly participants exhibited a negative correlation the downregulation of the ipsi-M1 facilitates the enhance- between these factors40). In addition, Seidler et al.41) stated ment of contra-M1 excitability and contributes to the that age-related atrophication of corpus callosum fibers motor learning of unimanual tasks, as attenuating the in- might be associated with this phenomenon because white hibitory inputs from the ipsi- to the contra-M1 via corpus matter volume reduces with age at a faster rate than gray callosum pathways results in reduced ipsi-M1 excitability, matter volume. Based on these findings, it could be con- which probably makes it easier to induce plasticity in the sidered that neural inputs derived from the contra-M1 into contra-M1 representation of the trained muscle. the ipsi-M1 that are transmitted via the corpus callosum are attenuated due to the atrophication of the corpus cal- Contribution of ipsi-M1 activity to muscle synergy losum fibers with advancing age, which would account for the greater activation of the ipsi-M1 observed during The selective muscle activity among agonist and an- unilateral voluntary movements in elderly people. tagonist muscles plays an important role in controlling skilled and coordinated movements. In this process, the antagonist muscle is suppressed via the inhibition of the Contribution of ipsi-M1 activity to motor learning corticospinal tracts innervating it when the agonist muscle It is considered that the M1 plays a key role in the early is voluntarily activated. As described above, even during stages of the acquisition of motor learning. In both hu- the performance of unilateral movements the moving limb mans and animals, motor learning involving the hands or is under the control of both M1. However, little detailed legs leads to alterations in the excitability of the contra- information is available about the role of the ipsi-M1 in M1 innervating the trained muscle, which is well known human motor control, although it is known that the ipsi- as plasticity42-46). However, to the best of our knowledge M1 predominantly influences the proximal limb rather there is not a lot of information about the details of the re- than the distal limb. Studies involving interventional non- lationship between motor learning and ipsi-M1 activity. A invasive brain stimulation with high-frequency rTMS human study that used a disruptive TMS technique found (i.e., theta burst stimulation, TBS) or transcranial direct that applying TMS over the dominant left M1 resulted current stimulation (tDCS) of the ipsi-M1 have shown in greater disruption of complex ipsilateral unimanual that the downregulation of ipsi-M1 excitability induced finger tasks than the application of TMS over the non- by these NBS techniques improved muscle synergy in dominant right M1 in right-handed participants47). This the proximal muscles of healthy participants23,50). In par- indicates that the left M1 is more involved in performing ticular, MEPs in the biceps brachii (BB) were facilitated ipsilateral movements than the right M1 in right-handed when the participants performed elbow flexion because participants. In other words, the left M1 contributes to ip- the BB acts as an agonist during this movement. On the silateral motor control systems during the performance of other hand, MEPs in the BB were suppressed when the unilateral movements with the left hand, but the right M1 participants performed forearm pronation because BB does not make a similar contribution when the right hand acts as an antagonist during this movement. When cath- is voluntarily activated. Suzuki et al. used a two-ball- odal tDCS (c-tDCS), which induced inhibitory changes in rotation task, which could be performed with the right or M1 excitability, was applied over the ipsi-M1 innervating JPFSM: Contribution of ipsilateral motor cortex to human motor control 301 the BB, MEPs induced in the BB during forearm prona- formation regarding the involvement of the cortical level tion were selectively suppressed23). In addition, in another showing that the neural circuits of short- (SICI) and long- study involving patients who had suffered stroke the (LICI) interval intracortical inhibition are mediated by muscle synergy of paralyzed proximal upper limbs was cortical interneurons via γ-aminobutyric acid (GABA)54-56) improved by c-tDCS of the ipsi-M1. These findings indi- and do not directly converge on the corticospinal tract57). cate that ipsi-M1 activity contributes to muscle synergy In addition, it has been shown that administering a con- in the proximal upper limb. Regarding the mechanism by ditioning stimulus over the M1 at subthreshold intensity which c-tDCS improves the muscle synergy of proximal to activate these inhibitory circuits did not modulate the muscles, it was proposed that the ipsilateral reticulospinal H-reflex in the wrist flexor muscle54). These findings indi- tract (RST) originating from the ipsi-M1 is probably as- cate that the modulation of intracortical circuits occurs at sociated with alterations in muscle synergy that are medi- the cortical level. Several studies assessing the SICI and ated via propriospinal neurons (PN)21-23). Previous animal LICI circuits have shown that unilateral voluntary move- studies have shown that PN are present at the level of the ments resulted in significant modulation of the SICI or cervical 3rd and 4th segments (C3-C4) of the spinal cord. LICI within the ipsi-M17-9,58). Taken together, there is no These neurons directly project to the alpha-motoneurons doubt that changes in the MEP induced in the opposite (α-MN) in the forelimb and act as inhibitory or excitatory limb originate from the cortical level; however, we are not neurons51,52). It has been stated that the C3-C4 propriospi- able to completely rule out the involvement of subcortical nal system plays a key role in controlling visually-guided level pathways. Thus, compatible activation of both the reaching forelimb movements in animals51). Regarding cortical and subcortical regions is probably involved in the neural mechanisms underlying the improvements in this phenomenon, which might be dependent on the type proximal muscle synergy induced in response to c-tDCS of task being performed (i.e., fine motor or ballistic tasks) of the ipsi-M1, it was suggested that downregulation and/or the strength of the muscle contraction involved. of the ipsilateral M1-RST pathways disinhibits the PN, With regard to the relationships between ipsi-M1 activ- resulting in the suppression of the antagonist BB α-MN ity and IHI, we recently reported that unilateral isometric before forearm pronation22,23). voluntary index finger abduction led to an increase in ipsi-M1 excitability and a significant increase in short- latency IHI (SIHI) from the contra- to the ipsi-M1; i.e., Mechanisms underlying the modulation of ipsi-M1 activity IHI was significantly increased when an ISI of 10 ms was It is necessary to consider what types of neural path- employed, but no such increase in long-latency IHI (LIHI) ways contribute to the modulation of ipsi-M1 activity was observed, and IHI was not increased when an ISI of as well as the changes in the MEP induced in the oppo- 40 ms was used18). These findings indicate that SIHI from site limb during unilateral voluntary movements. These the contra- to the ipsi-M1 affects ipsi-M1 excitability mechanisms have gradually been clarified by studies in- (Fig. 2). Another study assessing the modulation of SIHI volving neurophysiological techniques. With regard to the during a fine motor task (i.e., using chopsticks) reported sites responsible for such phenomena, it was found that that both SIHI from the contra- to the ipsi-M1 and ipsi- during a unilateral rhythmic repetitive movement involv- M1 excitability were increased. Interestingly, both of the ing wrist flexion and extension the MEPs evoked in the abovementioned studies detected significantly increased relaxed opposite wrist muscle by TMS of the M1 were ipsi-M1 excitability together with strong IHI from the modulated, while the evoked potentials derived from the contra- to the ipsi-M1 during these tasks. One interpreta- descending tract at the level of the cervicomedullary junc- tion of these results is that interhemispheric inputs from tion remained unchanged. In addition, the Hoffman (H-) the contra-M1 might not project directly to the cortico- reflex of the relaxed wrist muscle, which can be used as spinal output neurons within the ipsi-M1. Using a triple- an indicator of spinal activity, was also modulated by the pulse TMS paradigm, it was established that even during unilateral rhythmic movement53). Another study suggested the resting state, SIHI inhibited SICI within the M1 of that MEP facilitation of the relaxed opposite limb prob- the test stimulus side (Fig. 3)59). Given that SIHI from the ably occurs at both the cortical and subcortical levels8). contra- to the ipsi-M1 inhibits SICI within the ipsi-M1, On the other hand, no excitability changes in the anterior it is conceivable that this inhibition of SICI results in the horn cells of the spinal cord, which can be assessed us- facilitation of ipsi-M1 excitability during the performance ing F-waves, were detected during the performance of of unilateral movements10,18,29). unilateral rhythmic index finger abduction at around 10% With regard to the relationship between sensory systems of maximal voluntary contraction (MVC)6). In addition to and ipsi-M1 activity, previous studies have examined this finding, the F-waves induced in the relaxed opposite whether peripheral afferent inputs produced by electrical first dorsal interosseous (FDI) muscle during unilateral stimulation of the unilateral ulnar nerve can alter ipsi-M1 isometric contraction of the FDI at 10 or 30% MVC did excitability, as assessed by single-pulse TMS. As a result, not differ from those observed during the resting state of it was found that muscle spindle-derived afferent inputs both arms18). Another possible explanation provided in- altered ipsi-M1 excitability in a manner that was depen- 302 JPFSM: Uehara K and Funase K dent on the frequency of electrical stimulation60). Al- sible for modulating ipsi-M1 activity. though this study did not completely explain the detailed The neural inputs that converge in the ipsi-M1 arise neural mechanisms underlying the modulation of the ipsi- not only from the contral-M1, but also from contralateral M1 excitability induced by unilateral afferent inputs, it motor-related areas, e.g., the dorsal premotor area (PMd), was demonstrated that marked modulation of ipsi-M1 ventral premotor area (PMv), and supplementary mo- excitability occurred 35 ms after electrical stimulation of tor area (SMA), and are transmitted via corpus callosum the unilateral ulnar nerve. This finding can be interpreted pathways. Anatomical studies involving non-human pri- as indicating that afferent inputs from the peripheral limbs mates have found that the interhemispheric callosal con- take around 20-25 ms to reach the contralateral senso- nections in the M1, SMA, PMd, and PMv excite homo- rimotor area, and that short latency inhibition of the in- topic areas in the opposite hemisphere62,63). A recent study terhemispheric pathways linking the bilateral M1 extends in which a paired-pulse TMS paradigm was used to assess this period by around 10 ms. Given that peripheral elec- connectivity between the contralateral PMd (conditioning trical stimulation during TMS stimulation of the ipsi-M1 stimulus) and the ipsi-M1 (test stimulus) during unilat- resulted in significant modulation of ipsi-M1 excitability eral rhythmic muscle contractions performed according after 35 ms (25 ms + 10 ms), afferent inputs transmitted to three different auditory cues (1, 2, and 3 Hz) demon- via the short latency corpus callosum pathways might be strated that PMd-M1 connectivity was modulated by the involved in the modulation of ipsi-M1 excitability60). frequency demand of the contractions. Furthermore, this It should be noted that the M1 for distal muscles, i.e., modulation was consistent with the modulation of ipsi- finger muscles, and proximal muscles, and for the triceps M1 excitability, indicating that ipsi-M1 excitability might brachii (TB), project different levels of SIHI61). In par- be modulated by neural inputs from the contralateral ticular, significant SIHI was observed from the M1 for PMd7). the finger and BB muscles, but was not observed for the TB in the same individuals. Thus, in the case of proximal Functional significance of ipsi-M1 activity during volun- muscles, corpus callosum pathways might not be respon- tary movement. An fMRI study by Loibl et al.30) dem-

A: Resting state B: Unilateral voluntary movement

Resting Resting Resting Active hemisphere hemisphere hemisphere hemisphere (ipsilateral) (contralateral) (ipsilateral) (contralateral) idline idline

TS M CS TS M CS

IN M1 IN M1 IHI10 IHI10

PTN PTN

IHI40 IHI40

Corticospinal tract Corticospinal tract

Fig. 2 Schematic illustration of the functional differences between SIHI and LIHI targeting the ipsi-M1 during complete rest in both arms (i.e., the resting state) (A) and unilateral muscle contraction (B). In the resting state, SIHI and LIHI were observed (solid lines). On the other hand, during unilateral muscle contraction, strong SIHI from the contra- to the ipsi-M1 was observed (bold- solid line), but LIHI was not (dashed line). Abbreviations: M1: primary motor cortex, IN: interneurons, CS: conditioning stimu- lus, TS: test stimulus, PTN: pyramidal tract neuron. JPFSM: Contribution of ipsilateral motor cortex to human motor control 303

Ipsilateral hemisphere Contralateral hemisphere (resting M1) (active M1)

SICI idline M

M1 IHI

IN Fig. 3 A hypothetical model that attempts to explain the observed increase in ipsi-M1 excitability and strong IHI (i.e., increased IHI) from the contra- to the ipsi- M1. Inhibitory interhemispheric inputs from the contra-M1 inhibit SICI within the ipsi-M1, and then ipsi-M1 excitability is facilitated by the disinhibi- tion of SICI. The closed (a-M1 inhibit SICI within PTN the ipsi-M1, and then ipsi-M1 excitability is facili- tated by the disinhibSICI: short interval intracortical inhibition, IN: interneurons, PTN: pyramidal tract neuron, M1: primary motor cortex, IHI: interhemi- spheric inhibition. For detailed explanations, see Daskalakis et al.59). This figure was modified from Daskalakis et al.59).

Corticospinal tract Corticospinal tract

onstrated that the ipsilateral SM1 activity induced during performed as well as the demands of the task, the ipsi-M1 unilateral rhythmic movement performed at the maximal directly or indirectly contributes to human motor control possible frequency was negatively correlated with the during the performance of unilateral voluntary move- performance score in elderly, but not in younger subjects. ments. However, further study is required to improve our In addition, the ipsilateral SM1 activity induced in the el- understanding of the functional significance of ipsi-M1 derly subjects during a precision grip task also exhibited activity. a negative correlation with the performance score. It is Hübers et al. used a TMS paradigm to investigate the suggested that ipsilateral SM1 activity might be closely functional significance of ipsi-M1 activity. In particular, associated with task failure or unstable performance in they examined whether unwanted muscle activity (i.e., elderly subjects. In other words, it is likely that excessive mirror activity, MA) of the opposite limb during unilateral ipsi-M1 activity disrupts motor performance with advanc- muscle contractions is associated with IHI from the con- ing age. Conversely, as described earlier, performing a tra- (i.e., active M1) to the ipsi-M1 (i.e., resting M1)65). As fine motor task involving the use of chopsticks resulted a result, they found that the magnitude of the IHI target- in increased ipsi-M1 excitability compared with perform- ing the ipsi-M1 was negatively correlated with MA, i.e., ing a mimicking task without chopsticks9). Therefore, the participants who exhibited little MA displayed strong IHI degree of ipsi-M1 excitability induced during unilateral and vice versa. This novel finding might be indicative of rhythmic muscle contractions is probably dependent on another functional role of ipsi-M1 activity; i.e., as well as the difficulty of the task. For example, greater ipsi-M1 suppressing ipsi-M1 activity, inhibitory inputs converging excitability was induced during a high difficulty rhythmic on the ipsi-M1 via corpus callosum pathways might pre- task than during a similar low difficulty task7). In a previ- vent increases in MA in the opposite limb. ous study in which high-frequency of rTMS (TMS deliv- ered at a frequency of 15 Hz and suprathreshold intensity) Conclusions was used to disrupt ipsi-M1 activity, the disruptive stimu- lation led to an increase in timing errors during sequenced In this article, we reviewed and discussed the findings movements involving the pressing of piano keys with of previous studies that examined ipsi-M1 activity in- the four ipsilateral fingers64). Taken together, it can be duced in humans during active tasks involving unilateral stated that although it depends on the type of task being limb movements from neurophysiological and neuroim- 304 JPFSM: Uehara K and Funase K aging viewpoints. 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